Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000588536 | SCV000697883 | uncertain significance | not provided | 2017-01-03 | criteria provided, single submitter | clinical testing | Variant summary: The DSG2 c.14C>T (p.Pro5Leu) variant involves the alteration of a non-conserved nucleotide, which 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP), nor has it been, to our knowledge, reported in affected individuals via publications and/or clinical diagnostic laboratories/databases. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)." |
| Ambry Genetics | RCV000619285 | SCV000737791 | uncertain significance | Cardiovascular phenotype | 2016-11-09 | criteria provided, single submitter | clinical testing | The p.P5L variant (also known as c.14C>T), located in coding exon 1 of the DSG2 gene, results from a C to T substitution at nucleotide position 14. The proline at codon 5 is replaced by leucine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase (dbSNP) as rs530517936, but was absent from population based-cohorts in the Exome Aggregation Consortium (ExAC), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project databases. In the ESP, this variant was not observed in 5552 samples (11104 alleles) with coverage at this position, but sequencing depth was low. This amino acid position is poorly conserved in available vertebrate species, and leucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001853986 | SCV002140958 | uncertain significance | Arrhythmogenic right ventricular dysplasia 10 | 2022-08-09 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5 of the DSG2 protein (p.Pro5Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 496147). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |